Neuronal conduction across synapses in the mammalian central nervous system (CNS) is facilitated by a wide array of neurotransmitters. These neurotransmitters, upon release from the presynaptic neuron, can be either inhibitory or excitatory in action, depending upon whether they hyperpolarize or depolarize the postsynaptic neuron, respectively. Glutamic acid and aspartic acid have been identified as the major millisecond excitatory neurotransmitters in the mammalian CNS by R. L. Johnson et al., J. Med. Chem., 31, 2057 (1988). Five excitatory amino acid (EAA) receptor subtypes have been characterized so far. receptor subtypes have been characterized so far. See D. J. Monaghan et al., Annu. Rev. Pharmacol. Toxicol., 29, 365 (1989). These are the NMDA, AMPA, kainate, metabotropic, and L-AP4 receptors. The first three EAA receptor types directly gate ion channels, while the last two receptor types operate via second-messenger systems.
L-Quisqualic acid (1), an amino acid first isolated from the seeds of Quisqualis indica L., is a unique compound in that it is able to function as an agonist at multiple EAA receptor subtypes in the CNS. ##STR2## It has high affinity for the kainate, AMPA, and the metabotropic receptors. For example, see J. D. Davies et al., J. Physiol., 75, 641 (1979); E. D. London, Mol. Pharmacol., 15, 492 (1979); T. Honore et al., J. Neurochem., 38, 173 (1982); D. D. Schoepp et al., J. Neurochem., 50, 1605 (1988) and M. Recasens et al., Neurochem. Int., 13, 463 (1988). L-Quisqualic acid also inhibits the Ca.sup.2+ /Cl.sup.- -dependent glutamic acid uptake system in brain synaptic plasma membrane preparations and an N-acetyl .alpha.-linked acidic dipeptidase which hydrolyzes the brain dipeptide Ac-Asp-Glu-OH. See, R. Zaczek et al., Neuropharmacol., 26, 281 (1987) and M. B. Robinson et al., J. Biol. Chem., 262, 14498 (1987).
Recently, L-quisqualic acid has been shown to produce a 30-100-fold sensitization of CA1 neurons in rat hippocampal slices to depolarization (excitation) by D- or L-2-amino-4-phosphonobutanoic acid (AP4) and related phosphonates. See, M. B. Robinson et al., Brain Res., 381, 187 (1986) and E. R. Whittemore, Brain Res., 486, 146 (1989). This phenomenon, which has been termed the QUIS effect, appears to be widely distributed, and has been reported for neurons of the CA1 region in the rat and guinea pig brain and the medial perforant path, the lateral olfactory tract, and the cingulate cortex in rat brain. See E. R. Whittemore et al., Brain Res., 489, 146 (1989) and M. J. Sheardown et al., Eur. J. Pharmacol., 148, 471 (1988). E. R. Whittemore et al., Eur. J. Pharmacol., 192, 435 (1991) have reported that the QUIS effect can be blocked by a brief exposure of CA1 neurons to L-homocysteinesulfinic acid, L-.alpha.-aminoadipic acid, or L-serine O-sulfate. These compounds have been ntermed "preblockers" since they are able to block the QUIS effect even when they are removed from the incubation chamber prior to treatment of the slices with L-quisqualic acid. These same compounds are also capable of reversing the QUIS effect after it has been induced. Thus, these compounds are also referred to as "reversers." The AP4 site which is sensitized by L-quisqualic acid and the site to which L-quisqualic acid binds in order to bring about this sensitization are novel sites of action different from the classical AMPA and L-AP4 sites (M. K. Schulte et al., Brain Res., 582, 291 (1992)).
Since the dramatic increase of neuronal excitability manifested by the QUIS effect may have significance for understanding and modifying the mechanisms of neuronal plasticity that occur during learning and memory and for controlling the changes of excitability that occur in disease states such as epilepsy, a need exists for novel bioactive analogs of L-quisqualic acid.